Prostate Cancer
Conditions
Keywords
adenocarcinoma of the prostate, stage III prostate cancer, stage IV prostate cancer, recurrent prostate cancer
Brief summary
RATIONALE: Androgens can cause the growth of prostate cancer cells. Drugs, such as ketoconazole, may stop the adrenal glands from making androgens. Lenalidomide may stop the growth of prostate cancer by blocking blood flow to the tumor. Giving ketoconazole and hydrocortisone together with lenalidomide may be an effective treatment for prostate cancer. PURPOSE: This phase II trial is studying how well giving ketoconazole and hydrocortisone together with lenalidomide works in treating patients with prostate cancer that did not respond to hormone therapy.
Detailed description
OBJECTIVES: Primary * Determine the objective response frequency in patients with hormone-refractory progressive prostate cancer treated with ketoconazole, hydrocortisone, and lenalidomide. Secondary * Determine the effect of this regimen on time to clinical progression in these patients. * Determine the safety of this regimen in these patients. * Determine the effects of this regimen on serum cytokines, including tumor necrosis factor-alpha, basic fibroblast growth factor, plasma soluble interleukin (IL)-2 receptor, IL-8, and IL-12, as well as serum vascular endothelial growth factor levels in these patients. * Determine the co-stimulatory effects of this regimen on dendritic cells and CD4-positive, CD25-positive, T-regulatory cells in these patients. OUTLINE: This is a nonrandomized, open-label study. Patients receive oral ketoconazole 3 times daily and oral hydrocortisone twice daily on days 1-28 and oral lenalidomide once daily on days 1-21. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection periodically during study for evaluation of prostate cancer-specific immune response. Blood samples are assessed by serum analysis, flow cytometry, real-time PCR, and enzyme-linked immunosorbent assay techniques to detect and quantify different cytokines, antiangiogenic markers, dendritic cells, and specific T-regulatory cells. After completion of study therapy, patients are followed at 30 days. PROJECTED ACCRUAL: A total of 34 patients will be accrued for this study.
Interventions
DRUGketoconazole
400 tid
DRUGlenalidomide
Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle.
DRUGtherapeutic hydrocortisone
20mg qam 10mg qhs
Sponsors
Case Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
PATIENTS WITH PROSTATE CANCER PROGRESSIVE AFTER ANDROGEN DEPRIVATION Inclusion Criteria Understand and voluntarily sign an informed consent form. Age 18 years at the time of signing the informed consent form. Histologically confirmed adenocarcinoma of the prostate. Testosterone less than 50 ng/dL. Patients must continue primary androgen deprivation with an LHRH analogue if they have not undergone orchiectomy. All previous cancer therapy, including radiation, and surgery, must have been discontinued at least 4 weeks prior to receive first dose of study drug. Progressive disease after androgen deprivation.
Exclusion criteria
Prior systemic chemotherapy for hormone refractory prostate cancer. Prior neoadjuvant and adjuvant chemotherapy are allowed when completed at least 12 months prior to enrollment. Prior ketoconazole, aminoglutethimide or corticosteroids for the treatment of progressive prostate cancer. Prior immunotherapy including, but not limited to, vaccines, Thalidomide, and or Lenalidomide like agents. Supplements or complementary medicines/botanicals are not permitted while on protocol therapy, except for any combination of the following: conventional multivitamin supplements selenium lycopene soy supplements Patients should review the label with their doctor prior to enrollment, and discontinue disallowed agents prior to study enrollment Serious intercurrent infections or non-malignant medical illnesses including autoimmune disorders that are uncontrolled. Psychiatric illnesses/social situations that would limit compliance with protocol requirements. Evidence of CNS (brain or Leptomeningeal) metastases or large pleural/pericardial effusions. Known contraindication to receive Ketoconazole or Lenalidomide Concurrent use of ketoconazole with statin compounds is absolutely contraindicated. Thus, patients receiving Statin drugs (fluvastatin, atorvastatin, and simvastatin) should discontinue them for at least 7 days before starting ketoconazole. Patients taking astemizole, terfenadine, or cisapride, rifampin or isoniazid are not eligible, unless they agreed to completely discontinue those agents. In that case, any of these agents should be discontinued at least 7 days prior to start therapy with Ketoconazole. Use of any other experimental drug or therapy within 28 days of baseline. Known hypersensitivity to thalidomide or its analogues. Any prior use of Lenalidomide. Known positive for HIV or infectious hepatitis, type A, B or C. Disease free of prior malignancies for 5 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma insitu of the breast.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease | 28 days | Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) \>= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) \>= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | One year (12 months) after start of treatment | Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) \>= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) \>= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease. |
| Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0 | Up to 30 days after discontinuation of treatment | Patients will be evaluated for toxicity every 2 weeks during the first cycle. Thereafter, evaluations will be done every 28 days or more frequently if clinically indicated. |
| Change in Immune Response From Baseline | Week 8 | The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the levels of CD4+ FoxP3+ Regulatory T cells |
| Ratio of Change in Immune Response From Baseline | Week 8 | The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the ratio of BDCA-2 to BDCA-1 cells |
Countries
United States
Participant flow
Recruitment details
Thirty seven (37) patients were screened from Cleveland Clinic and University Hospitals in the Cleveland area from February 2007 to April 2009.Three patients were not eligible.
Participants by arm
| Arm | Count |
|---|---|
| Ketoconazole Plus Lenalidomide Ketoconazole will be administered daily on days 1-28 of the cycle at a dose of 400mg po tid with hydrocortisone 20mg po every morning and 10mg po at bedtime. Hydrocortisone will be given on a continuous basis. Lenalidomide will be administered daily at a dose of 25mg po qd on days 1-21 of the cycle. | 34 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 5 |
| Overall Study | Death | 1 |
| Overall Study | Withdrawal by Subject | 5 |
Baseline characteristics
| Characteristic | Ketoconazole Plus Lenalidomide |
|---|---|
| Age, Customized 40-49 years | 2 participants |
| Age, Customized 50-59 years | 5 participants |
| Age, Customized 60-69 years | 10 participants |
| Age, Customized 70-79 years | 11 participants |
| Age, Customized 80-89 years | 6 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 33 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 30 Participants |
| Region of Enrollment United States | 34 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 34 / 34 |
| serious Total, serious adverse events | 12 / 34 |
Outcome results
Primary
Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease
Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) \>= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) \>= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.
Time frame: 28 days
Population: All patients who completed the study
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ketoconazole Plus Lenalidomide | Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease | Partial Response | 7 participants |
| Ketoconazole Plus Lenalidomide | Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease | Progressive Disease | 7 participants |
| Ketoconazole Plus Lenalidomide | Number of Patients With a Partial Response, Progressive Disease, or Stable Disease Based on Prostate-Specific Antigen (PSA) or Measurable Disease | Stable Disease | 9 participants |
Secondary
Change in Immune Response From Baseline
The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the levels of CD4+ FoxP3+ Regulatory T cells
Time frame: Week 8
Population: All patients who completed the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketoconazole Plus Lenalidomide | Change in Immune Response From Baseline | 0.18 cells/ul | Standard Deviation 0.31 |
Secondary
Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0
Patients will be evaluated for toxicity every 2 weeks during the first cycle. Thereafter, evaluations will be done every 28 days or more frequently if clinically indicated.
Time frame: Up to 30 days after discontinuation of treatment
Population: All patients who received at least one treatment in the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ketoconazole Plus Lenalidomide | Number of Patients With Grade 3 and 4 Toxicity as Assessed by NCI CTCAE v3.0 | 19 participants |
Secondary
Ratio of Change in Immune Response From Baseline
The pattern of immune response by assessing T cell and dendritic cell markers, specifically by measuring the ratio of BDCA-2 to BDCA-1 cells
Time frame: Week 8
Population: All patients who completed the study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketoconazole Plus Lenalidomide | Ratio of Change in Immune Response From Baseline | -0.39 ratio | Standard Deviation 1.44 |
Secondary
Time to Progression
Patients will be evaluated for clinical benefit monthly with PSA values.Patients who are benefiting from treatment are eligible for additional cycles of treatment. Thereafter, therapy will continue until criteria for progressive disease are met. Response is based on the RECIST criteria from the National Cancer institute. Complete Response (CR) disappearance of all target lesions; Partial Response (PR) \>= 30% decrease in the sum of the longest diameter of target lesions from baseline; Progressive Disease (PD) \>= increase in the sum of the longest diameter of target lesions from baseline; Stable Disease (SD) neither sufficient for partial response nor sufficient increase for progressive disease.
Time frame: One year (12 months) after start of treatment
Population: Patients with disease progression
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Ketoconazole Plus Lenalidomide | Time to Progression | 3 Months |